Phthalimide derivatives and process



United States In one of our earlier specifications there are described aromatic discarboxylic acid imides of the general formula in which Xrepresents a divalent aromatic residue, which may be substituted by halogen, Y represents an alkylene group having at most four carbon atoms, R and R each represent an alkyl, cycloalkyl or aralkyl group and R may also represent a hydrogen atom, the alkyl groups being of low molecular weight, or R and R together with the nitrogen atom form the residue of a saturated 5- or 6-membered ring, and salts thereof. These compounds possess valuable analgesic and antiphlogistic properties.

The present invention provides phthalimide derivatives of the general formula R1 \N R g @oo-on oH N o0 l in which R represents a hydrogen or halogen atom or a hydroxy or alkoxy group, R represents a hydrogen atom or an alkyl group of low molecular weight, R and R represent alkylor aralkyl groups, or R and R together with the nitrogen atom form the residue of a saturated 5- or 6-membered ring system, and which derivatives also have excellent antiphlogistic and good analgesic properties.

The present invention also provides a process for the manufacture of the above-mentioned phthalimide derivatives, wherein an acyl derivative of an N-phenyl-phthalimide of the general formula in which R and R have the meanings given above is reacted with formaldehyde or a compound yielding formaldehyde and with a secondary amine of the general formula in which R, and K; have the meanings given above; or an acylaniline of the general formula in which R R R and R have the meanings given above, is reacted with a phthalic acid of the general formula COOH 1 COOH in which R has the meaning given above or with a functional derivative of such a phthalic acid in known manner.

As acyl derivatives which may be used in the process.

of this invention being capable of condensing with formaldehyde and a secondary amine, there may be mentioned, for example, -2- 3- or 4-phthalimido-acetopheuone, 4- phthalimido-propiophenone, 4 phthalimido butyrophe none, 3-phthalimido-valerophenone, 4-phthalimido-isovalerophenone, 4-(3-chloro-phthalimido)-acetophenone, l

4-(3-hydroxy-phthalimido)-acetophenone, 4-(4-chlorophthalimido)-acetophcnone or 3-(4-methoxy-phthalimi do)-propiophenone.

amine and benzylmethylamine.

Examples of acylanilines having basically substituted .v acyl residues, as may be used for the reaction With're-v active derivatives of phthalic acid, are 4-amino-fl-dimethylamino-propiophenone, 4-amino-fi-piperidino-propiophenone, 3-amino-a-methyl-fi-diethylamino-propiophenone,

4-amino-fl-piperidino-butyrophenone, Z-amino-fi-morpholino-valerophenone and 4-amino-B-(Z-methyl-piperidino)- a-ethyl-caprophenone.

Examples of reactive derivatives of phthalic acid, which may be used for reaction with the aniline deriva- 1 tives having an amiuo-acylated phenyl nucleus are, phthalic anhydride, 4-oxy-phthalic anhydride, halogenated phthalic anhydrides, such, for example, as 4-chlorophthalic anhydride, 3-methoxy-phthalic acid dichloride,

3-chloro-phtha1ic acid dichloride, 4-ethoxy-phthalic acid dimethyl ester, 4-ethoxy-phthalic acid diethyl ester, 3-

methoxy-phthalic acid dibutyl ester or 3-chloro-phthalic acid dipropyl ester.

The condensation of the acyl derivative of an N-phenylphthalimide with formaldehyde or a compound yielding formaldehyde, such as para-formaldehyde, and with a secondary amine is carried out in known manner by the Mannich-base-condensation reaction. Advantageously,

glacial acetic acid is used as solvent and the formaldehyde used is an excess of para-formaldehyde which is easy to handle. Advantageously, the secondary amine is used in the form of a hydrohalide, so that the hydrohalide of the condensation product is obtained directly as endproduct. Itiisalso advantageous to mix the starting materials in glacial acetic acid and to stir the mixture thus obtained for a few hours at a slightly raised temperature.

Preferably, the reaction is conducted at a temperature i within the range of C. to C. Furthermore, it

is advantageous to add the para-formaldehyde portion- The reaction product isobtained in the form of its hydro-halide which crystallises' r out after cooling the reaction solution, sometimes only after concentrating the solution, and in certain cases only r wise throughout the reaction.

after the addition of alcohol and ether. The product is purified in the usual manner by recrystallisation from a suitable solvent, such, for example, as acetic acid, alcohol or Water.

in itself known.

Patented Sept. 26, 1961 The reaction of the acylaniline, having a bas-' r ically substituted acyl residue, with a phthalic acid or a; '2 reactive derivative thereof is also conducted by a method at Thus, by heating the free phthalic' acid or a reactive derivative thereof, advantageously :1

3 the anhydride, with the aniline derivative at a temperature usually above 100 C., water is split off and the corresponding phthalimido compound is obtained. An especially advantageous form of the process is to boil the aminoacylated aniline in the form of its hydrochloride under reflux with phthalic anhydride in glacial acetic acid. The reaction usually takes about 2 hours, and the product is obtained directly in the form of its hydrochloride. It is also possible to carry out the process by reacting the acylated aniline containing a free amine group with phthalic anhydride in alcohol, acetone, dioxane, or dimethyl formamide usually at a temperature below 100" C. so that the corresponding phthalamidic' acid is obtained which then undergoes ring closure to the phthalimide by heating it at a temperature usually above 100 C., advantageously by boiling" it' in glacial acetic acid. The reaction products, which are thus obtained in solution as their acetic acid salts, can either be isolated as such by reduction in the volume of solutiomor', by treating with other organic or inorganic acids may be converted into other salts. Forthis purpose, suitable organic acids are, for example, malonic acid, propionic acid, lactic acid, succinic acid, tartaricac'id, ni'aleicfacid', fumaric acid, citric acid, malic acid, salicylic acid, hydroxy-ethane-sulphonic acid, aceturic' acid, of ethylenediamine'tetra-acetic acid, and inorganic acids are, for example, hydrohalic' acids, such as hydrochloric acid or hydrobromic acid, and" sulphuric acid, phosphorioacid'or amidosulphonic acid.

Thenew compounds obtained bythe' process of the present invention are useful medicaments; which are'distinguished by having antiphlogistic and good analgesic 4-phthalimidop piperidino propioph'enone properties; hydrochloride, for example, has twice the analgesic'ao tivityofdimethyl-amino=phenyl-dimethyl-pyrazolone; Tests 'carried out on the mouse'for' the determination of analgesia by the method devised by Wolff, Hardy, Goodell (see Journal ofChemical Investigation, vol.- 19, pages-649 and 659 (1940) and vol. 20,'page 63 (1941)) showed that with a dose of '40 mgJ/kg. s.c." the"activ ity was considerably prolonged, and that 'witha dose of 50 mg. /kg. s.c. pain was substantially overcome. purpose of oral administration, good analgesia is obtained with a dose of 100 mg./kg. Anantiphlogi'stic action 45 already observed in the rat with a dose of 50 mg;/kg.

The new'compounds of this inventioncan be used as such or in some cases advantageously in the formof their acid addition salts, or if desired, in admixture with the usual pharmaceutical carriers, such as starch, lactose, tragacanth, or magnesium stearate, for the preparation of pharmaceuticals, or made up into various'forms suitable for administration, such as tablets, dragees,'capsules,

drops, suppositories, or ampoulesj. The'preparationsare preferably administered per os.

The following examples illustrate the invention? Example 1 53 grams of 4-phthalimido-acetophenone, '60 gr'ams' o f' For'the piperidine hydrochloride and 10 grams of para-formaldehyde were stirred with 400 cc. ofglacial acetic acid for 2 hours at90 C.' A further 10 grams of para-formalde hyde were then added to the mixture which was stirred for a further 1%. hour at the same temperature; The reaction solution was then cooled and, after the addition of 100 cc. of alcohol and one litre of ether, 61.5 grams of '4-phthalimido-;3-piperidino-propiophenone hydrochlo ride were obtained, which, after recrystallisation "from water,- melted at 228 to 229" C."

Example 2 Sir/grams of 4-phthalimido acetophenone were" heated with 30' grams of pyrrolidine hydrochloride and 9grams of-para-formaldehyde in 200cc. of glacial acetic acid for 3 hours at the boil under reflux. On cooling the reaction solution, 50 grams of 4-phthalimido fl-pyrrolidinc-propio-' phenonezhydrochloride. crystallised outewhich, after re-- 56 grams of 4-phthalimido propiophenone were stirred with 60 grams of piperidine hydrochloride and 10 grams of paiai formaldehyde in 500 cc. of glacial.acetic acid at 90 C., until a clearsolution was obtained (ca. 30 minutes). A further 10 grams of para-"formaldehyde were then added and stirring was continued at C. for a further 2 hours.v The reaction solution was concentrated to half its volume under reduced pressure and then allowed to cool. 66.4 grams of 4-phth'alimido-wmethylfl-piperidino-propiophenone hydrochloride were obtained, which, after recrystallisation from water, had a melting point of 205-206 C;

Example 4 53 grams of 4-phthalimido acetophenone,60 gramssr diethylamine hydrochloride and 10 grams of para-formaldehyde in 500 cc. of glacial-acetic acid were stirred for 30 minutes at 90 C., and then afurther 10 grams of para-formaldehyde were added to the reaction mixture. After stirring for a further 2 hours at about 90? C., 250 cc. of glacial acetic acid were distilled ofi under water pump vacuum; After cooling the reaction solution; 35.7 grams of 4-phthalimido-p-diethylamino propiophenono hydrochloride c'arystallised' out, which; after recrystallisation from glacial acetic 'acidyhada' melting'point of 200- 202- C;

By using 60 grams of-morpholine'hydrochloride instead ofdiethylarnine hydrochloride in the above T experiment,

A mixture comprising 53 grams of 3-phthalin1ido-acetophenone, 60 grams of piperidine hydrochlorideand 10 grams of para-formaldehyde was stirred for 2 /2 hours in 400 CC.Of glacial acetic acid at 90 C. On cooling the reaction solution, 53.3 grams of the hydrochloride of 3-phthalimido-fl-piperidino propiophenone were obtained which, afterrecrystallisation from water, had a melting point of 220 C.

Exa'inple 6 15 grams of 4-amino-y8-piperidind"propiophenone dihydrochloride and 7.5 grams of 'phthalic anhydride were heated under reflux in cc. of glacial acetic acid for 2 hours. On cooling, 9.3 grams of asalt crystallised out which was identical with the product obtained in Example 1, namely,- -4 phthalimido-fi-pipefidino propiophenone hydrochloride. By using the monohydrochloride instead of thedihydrochloride of 4-amino-p-piperidino propiophenone, 4-phthalimido-fi-piperidino-propiophenone hydrochloride was obtained in a yield of about 90% of theory.

Example 7 60 grams of 4-(4-chloro-phthalimido)-acetophenone, 60 grams of piperidine hydrochloride and 10 grams of para-formaldehyde were stirred for 2 hours in 750 cc. of glacial acetic acid at'about 90 C. On'cooling,64 grams of 4-(4-chloro-phthalimido)-/3-piperidino-propiophenone hydrochloride were obtained which, after recrystallisation from glacial acetic acid, had a melting" point of 232 C. to 234 C.

We claim:

1. A member of the group consisting of phthalimide derivatives ofthe formula co\ m "oo onn V00 Q I C P R, R, inwhich R is a member-of the group consisting of hydra gen and chlorine, R is a member of the group consisting of hydrogen and alkyl groups of one to three carbon atoms and R and R are members of the group consisting of alkyl groups of one to four carbon atoms and, together with the nitrogen atom, members of the group consisting of pyrrolidine, piperidine and morpholine, and non-toxic acid addition salts of these compounds.

2. The compound of the formula 3. The compound of the formula 4. The compound of the formula 5. The compound of the formula N nMHMHPF o 00 6. The compound of the formula CO /N C0-CH2-CHaNN H 00 1 References Cited in the file of this patent Ghosh et al.: J. Indian Chem. Soc., vol. 30 (1953), pages 863-6. 

1. A MEMBER OF THE GROUP CONSISTING OF PHTHALIMIDE DERIVATIVES OF THE FORMULA
 5. THE COMPOUND OF THE FORMULA 